8 results on '"Vahtola, Erik"'
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2. Trender inom utvecklingen av onkologiska läkemedel
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Vahtola, Erik, Mustonen, Mika, Eero Mervaala / Ansvarig forskare, HUS Cancercentrum, Avdelningen för cancersjukdomar, and HUS sjukvårdsområde
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317 Farmaci ,Drug Development ,Biomarkers, Tumor ,Antineoplastic Agents ,3122 Cancersjukdomar ,+trends - Abstract
English summary
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- 2019
3. Sirtuin1-p53, forkhead box O3a, p38 and post-infarct cardiac remodeling in the spontaneously diabetic Goto-Kakizaki rat
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Kytö Ville, Kaheinen Petri, Raivio Johanna, Merasto Saara, Forstén Hanna, Louhelainen Marjut, Vahtola Erik, Tikkanen Ilkka, Levijoki Jouko, and Mervaala Eero
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Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Background Diabetes is associated with changes in myocardial stress-response pathways and is recognized as an independent risk factor for cardiac remodeling. Using spontaneously diabetic Goto Kakizaki rats as a model of type 2 DM we investigated whether post-translational modifications in the Akt - FOXO3a pathway, Sirt1 - p53 pathway and the mitogen activated protein kinase p38 regulator are involved in post-infarct cardiac remodeling Methods Experimental myocardial infarction (MI) was induced by left anterior descending coronary artery ligation in spontaneously diabetic Goto-Kakizaki rats and non-diabetic Wistar controls. Cardiac function was studied by echocardiography. Myocardial hypertrophy, cardiomyocyte apoptosis and cardiac fibrosis were determined histologically 12 weeks post MI or Sham operation. Western blotting was used to study Caspase-3, Bax, Sirt1, acetylation of p53 and phosphorylation of p38, Akt and FOXO3a. Electrophoretic mobility shift assay was used to assess FOXO3a activity and its nuclear localization. Results Post-infarct heart failure in diabetic GK rats was associated with pronounced cardiomyocyte hypertrophy, increased interstitial fibrosis and sustained cardiomyocyte apoptosis as compared with their non-diabetic Wistar controls. In the GK rat myocardium, Akt- and FOXO3a-phosphorylation was decreased and nuclear localization of FOXO3a was increased concomitantly with increased PTEN protein expression. Furthermore, increased Sirt1 protein expression was associated with decreased p53 acetylation, and phosphorylation of p38 was increased in diabetic rats with MI. Conclusions Post-infarct heart failure in diabetic GK rats was associated with more pronounced cardiac hypertrophy, interstitial fibrosis and sustained cardiomyocyte apoptosis as compared to their non-diabetic controls. The present study suggests important roles for Akt-FOXO3a, Sirt1 - p53 and p38 MAPK in the regulation of post-infarct cardiac remodeling in type 2 diabetes.
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- 2010
- Full Text
- View/download PDF
4. Diabetic cardiomyopathy and post-infarct ventricular remodelling : Effects of levosimendan in a rodent model of type II diabetes
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Vahtola, Erik, University of Helsinki, Faculty of Medicine, Institute of Biomedicine, Helsingin yliopisto, lääketieteellinen tiedekunta, biolääketieteen laitos, Helsingfors universitet, medicinska fakulteten, biomedicinska institutionen, and Laine, Mika
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farmakologia - Abstract
Type 2 diabetes is a risk factor for the development of cardiovascular disease. Recently, the term diabetic cardiomyopathy has been proposed to describe the changes in the heart that occur in response to chronic hyperglycemia and insulin resistance. Ventricular remodelling in diabetic cardiomyopathy includes left ventricular hypertrophy, increased interstitial fibrosis, apoptosis and diastolic dysfunction. Mechanisms behind these changes are increased oxidative stress and renin-angiotensin system activation. The diabetic Goto-Kakizaki rat is a non-obese model of type 2 diabetes that exhibits defective insulin signalling. Recently two interconnected stress response pathways have been discovered that link insulin signalling, longevity, apoptosis and cardiomyocyte hypertrophy. The insulin-receptor PI3K/Ak pathway inhibits proapoptotic FOXO3a in response to insulin signalling and the nuclear Sirt1 deacetylase inhibits proapoptotic p53 and modulates FOXO3a in favour of survival and growth. --- Levosimendan is a calcium sensitizing agent used for the management of acute decompensated heart failure. Levosimendan acts as a positive inotrope by sensitizing cardiac troponin C to calcium and exerts vasodilation by opening mitochondrial and sarcolemmal ATP-sensitive potassium channels. Levosimendan has been described to have beneficial effects in ventricular remodelling after myocardial infarction. The aims of the study were to characterize whether diabetic cardiomyopathy associates with cardiac dysfunction, cardiomyocyte apoptosis, hypertrophy and fibrosis in spontaneously diabetic Goto-Kakizaki (GK) rats, which were used to model type 2 diabetes. Protein expression and activation of the Akt FOXO3a and Sirt1 p53 pathways were examined in the development of ventricular remodelling in GK rats with and without myocardial infarction (MI). The third and fourth studies examined the effects of levosimendan on ventricular remodelling and gene expression in post-MI GK rats. The results demonstrated that diabetic GK rats develop both modest hypertension and features similar to diabetic cardiomyopathy including cardiac dysfunction, LV hypertrophy and fibrosis and increased apoptotic signalling. MI induced a sustained increase in cardiomyocyte apoptosis in GK rats together with aggravated LV hypertrophy and fibrosis. The GK rat myocardium exhibited decreased Akt- FOXO3a phosphorylation and increased nuclear translocation of FOXO3a and overproduction of the Sirt1 protein. Treatment with levosimendan decreased cardiomyocyte apoptosis, senescence and LV hypertrophy and altered the gene expression profile in GK rat myocardium. The findings indicate that impaired cardioprotection via Akt FOXO3a and p38 MAPK is associated with increased apoptosis, whereas Sirt1 functions in counteracting apoptosis and the development of LV hypertrophy in the GK rat myocardium. Overall, levosimendan treatment protects against post-MI ventricular remodelling and alters the gene expression profile in the GK rat myocardium. Diabetes on sydän- ja verisuonisairauksien riskitekijä ja Suomessa diabetesta sairastaa arviolta puoli miljoonaa ihmistä. Diabeteksen hoito Suomessa vie jopa 15 prosenttia terveydenhuollon kustannuksista. Diabeteksen aiheuttamat haitalliset sydänvaikutukset ovat jääneet muiden tunnetumpien kohde-elinvaurioiden varjoon. Diabeettinen kardiomyopatia terminä osoittaa insuliiniresistenssin ja kroonisen hyperglykemian epäedullisia vaikutuksia sydämeen. Diabeettisessa kardiomyopatiassa vasen kammio uudelleenmuovautuu (remodelling-ilmiö) jolloin sydänlihassolut kasvavat (hypertrofia), sydänlihas on alttiimpi solukuolemalle (apoptoosi) ja sydänlihassolujen väliin muodostuu sidekudoslisää jolloin sydämen toiminta häiriintyy. Muun muassa näistä syistä johtuen diabetesta sairastavan sydäninfarkti on useammin fataali. Mekanismeiksi on ehdotettu sekä lisääntynyttä oksidatiivista stressiä että reniini-angiotensiinijärjestelmän lisääntynyttä aktiivisuutta. Aikaisemmin on selvitelty kahden signalointireitin osuutta pitkäikäisyydessä, solukuolemassa ja hypertrofiassa. Insuliinireseptori-PI3K/Akt signalointireitti estää proapoptoottista FOXO3a:ta ja Sirt1 -entsyymi estää proapoptoottista p53:a ja moduloi FOXO3a:ta ja lisää hypertrofiaa. Näiden signalointireittien osuutta diabeettisessa kardiomyopatiassa ei ole selvitetty. Levosimendaani on kalsiumherkistäjä jota käytetään laskimonsisäisenä lääkkeenä akuutin sydämen vajaatoiminnan pahenemisvaiheessa. Sillä on edullista vaikutusta sydämen pumppauskykyyn herkistämällä sydänlihassolun troponiini C:tä kalsiumille ja lisää verisuonen relaksaatiota avaamalla ATP-herkkiä kaliumkanavia. Kokeellisissa asetelmissa pitkäaikainen oraalinen levosimendaani parantaa sydämen pumppaustoimintaa ja vähentää sydämen uudelleenmuovautumista. Edullisten vaikutusten mekanismit sydämen uudelleenmuovautumisessa ovat epäselvät. Tässä työssä tutkin diabeettisen kardiomyopatian eri osa-alueita ml. sydämen toimintaa, hypertrofiaa, apoptoosia sekä fibroosia käyttäen Goto-Kakizaki (GK) rottaa joka on sisäsiittoisella menetelmällä tuotettu tyyppi 2 diabeteksen eläinmalli. Sydämen vajaatoiminta aikaansaatiin sitomalla vasenta kammiota suonittava, eteen laskeva (LAD) verisuonihaara. Levosimendaania annettiin 12 viikon ajan kokeellisen infarktin jälkeen sekä diabeettisille GK- että ei-diabeettisille Wistar rotille. Sydänlihaksesta tutkin FOXO3a, Sirt1 ja p53 proteiiniekspressioita sekä ilman sydäninfarktia että sydäninfarktin jälkeen. Levosimendaanin vaikutuksia sydämen geeniekspressioon tutkittiin mikrosirutekniikalla. Tulokset näyttivät että GK rotat kehittävät diabeettisen kardiomyopatian tuntomerkkejä ml. sydänlihassolujen hypertrofiaa, väliaineen sidekudoslisää sekä sydänlihassolujen apoptoottista sigalointia. Infarkti lisäsi edelleen sydämen uudelleenmuovautumista aiheuttaen pysyvästi lisääntynyttä apoptoosia sekä lisääntynyttä hypertrofiaa ei-diabeettisiin eläimiin verrattuna. GK rotan sydämessä FOXO3a:n fosforylaatio oli vähentynyt ja Sirt1 proteiinin ekspressio lisääntynyt. Levosimendaani vähensi sydänlihassolun apoptoosia ja hypertrofiaa sekä vaikutti usean geenin ilmentymiseen ml. mTOR ja Hpgd. Löydökset viittaavat siihen että diabeettisen kardiomyopatiaan liittyy sydämen stressireaktiota säätelevien Akt - FOXO3a ja Sirt1 - p53 signalointireittien muutoksia. Näiden säätelijöiden tiedetään osallistuvan sydänlihassolun lisääntyneeseen hypertrofiaan ja apoptoosiin joita tavattiin tässä tutkimuksessa. Kaiken kaikkiaan, levosimendaani suojasi diabeettista sydäntä infarktin jälkeiseltä sydämen uudelleenmuovautumiselta ja vaikutti sydämen geeniekspressioprofiiliin.
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- 2011
5. Sirtuin1-p53, forkhead box O3a, p38 and post-infarct cardiac remodeling in the spontaneously diabetic Goto-Kakizaki rat
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University of Helsinki, Institute of Biomedicine (-2009), University of Helsinki, Medicum, University of Helsinki, Clinicum, Vahtola, Erik, Louhelainen, Marjut, Forsten, Hanna, Merasto, Saara, Raivio, Johanna, Kaheinen, Petri, Kyto, Ville, Tikkanen, Ilkka, Levijoki, Jouko, Mervaala, Eero, University of Helsinki, Institute of Biomedicine (-2009), University of Helsinki, Medicum, University of Helsinki, Clinicum, Vahtola, Erik, Louhelainen, Marjut, Forsten, Hanna, Merasto, Saara, Raivio, Johanna, Kaheinen, Petri, Kyto, Ville, Tikkanen, Ilkka, Levijoki, Jouko, and Mervaala, Eero
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- 2010
6. Sirtuin1-p53, forkhead box O3a, p38 and post-infarct cardiac remodeling in the spontaneously diabetic Goto-Kakizaki rat
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Vahtola, Erik, primary, Louhelainen, Marjut, additional, Forstén, Hanna, additional, Merasto, Saara, additional, Raivio, Johanna, additional, Kaheinen, Petri, additional, Kytö, Ville, additional, Tikkanen, Ilkka, additional, Levijoki, Jouko, additional, and Mervaala, Eero, additional
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- 2010
- Full Text
- View/download PDF
7. Sirtuin1-p53, forkhead box O3a, p38 and postinfarct cardiac remodeling in the spontaneously diabetic Goto-Kakizaki rat.
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Vahtola, Erik, Louhelainen, Marjut, Forstén, Hanna, Merasto, Saara, Raivio, Johanna, Kaheinen, Petri, Kytö, Ville, Tikkanen, Ilkka, Levijoki, Jouko, and Mervaala, Eero
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PEOPLE with diabetes , *HEART dilatation , *CELL death , *HEART diseases , *CARDIAC arrest - Abstract
Background: Diabetes is associated with changes in myocardial stress-response pathways and is recognized as an independent risk factor for cardiac remodeling. Using spontaneously diabetic Goto Kakizaki rats as a model of type 2 DM we investigated whether post-translational modifications in the Akt - FOXO3a pathway, Sirt1 - p53 pathway and the mitogen activated protein kinase p38 regulator are involved in post-infarct cardiac remodeling Methods: Experimental myocardial infarction (MI) was induced by left anterior descending coronary artery ligation in spontaneously diabetic Goto-Kakizaki rats and non-diabetic Wistar controls. Cardiac function was studied by echocardiography. Myocardial hypertrophy, cardiomyocyte apoptosis and cardiac fibrosis were determined histologically 12 weeks post MI or Sham operation. Western blotting was used to study Caspase-3, Bax, Sirt1, acetylation of p53 and phosphorylation of p38, Akt and FOXO3a. Electrophoretic mobility shift assay was used to assess FOXO3a activity and its nuclear localization. Results: Post-infarct heart failure in diabetic GK rats was associated with pronounced cardiomyocyte hypertrophy, increased interstitial fibrosis and sustained cardiomyocyte apoptosis as compared with their non-diabetic Wistar controls. In the GK rat myocardium, Akt- and FOXO3a-phosphorylation was decreased and nuclear localization of FOXO3a was increased concomitantly with increased PTEN protein expression. Furthermore, increased Sirt1 protein expression was associated with decreased p53 acetylation, and phosphorylation of p38 was increased in diabetic rats with MI. Conclusions: Post-infarct heart failure in diabetic GK rats was associated with more pronounced cardiac hypertrophy, interstitial fibrosis and sustained cardiomyocyte apoptosis as compared to their non-diabetic controls. The present study suggests important roles for Akt-FOXO3a, Sirt1 - p53 and p38 MAPK in the regulation of post-infarct cardiac remodeling in type 2 diabetes. [ABSTRACT FROM AUTHOR]
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- 2010
- Full Text
- View/download PDF
8. Oral Treatment with Calcium Sensitizer Levosimendan Improves Survival and Prevents Cardiac Remodeling in Hypertensive Dahl/Rapp Rats.
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Vahtola, Erik, Louhelainen, Marjut, Merasto, Saara, Kaheinen, Petri, Leskinen, Hanna, Finckenberg, Piet, Levijoki, Jouko, Pollesello, Piero, Haikala, Heimo, and Mervaala, Eero
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- 2005
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